Temozolomide Treatment Alters Mismatch Repair and Boosts Mutational Burden in Tumor and Blood of Colorectal Cancer Patients

Crisafulli, Giovanni; Lazzari, Luca; Pietrantonio, Filippo; Amatu, Alessio; Macagno, Marco; Barault, Ludovic; Cassingena, Andrea; Bartolini, Alice; Luraghi, Paolo; Mauri, Gianluca; Battuello, Paolo; Personeni, Nicola; Zampino, Maria Giulia; Pessei, Valeria; Vitiello, Pietro Paolo; Tosi, Federica; Idotta, Laura; Morano, Federica; Valtorta, Emanuele; Bonoldi, Emanuela; Germano, Giovanni; Nicolantonio, Federica Di; Marsoni, Silvia; Siena, Salvatore; Bardelli, Alberto

doi:10.1158/2159-8290.cd-21-1434

Cited by 52 publications

(24 citation statements)

References 92 publications

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“…As shown in Figures 4A, B , the IC50 of the TMEscore-H group was not significantly different to that of the TMEscore-L group for cisplatin and docetaxel (P>0.05), but was significantly different for 5-fluorouracil, gemcitabine, and paclitaxel ( Figures 4C–E ). Furthermore, five chemotherapy drugs (temozolomide ( 24 ), pyrimethamine ( 25 ), lapatinib ( 26 ), doxorubicin ( 27 ), and ruxolitinib ( 28 )), which are reported to be associated with the treatment of CRC, showed significant differences between the TMEscore-H and TMEscore-L groups ( Figures 4F–J ). Thereafter, the expression levels of six known immune checkpoint inhibitors, namely PD1 (PDCD1), PD-L1, PD-L2 (PDCD1LG2), CD80, CD86, CTLA4, and CD274, were compared based on the TMEscore clusters.…”

Section: Resultsmentioning

confidence: 99%

Tumor-infiltrating immune cells based TMEscore and related gene signature is associated with the survival of CRC patients and response to fluoropyrimidine-based chemotherapy

Guo

Lei

et al. 2022

Front. Oncol.

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BackgroundTumor-infiltrating immune cells (TIICs) are associated with chemotherapy response. This study aimed to explore the prognostic value of a TIIC-related tumor microenvironment score (TMEscore) in patients with colorectal cancer (CRC) who underwent chemotherapy and construct a TMEscore-related gene signature to determine its predictive value.MethodsGene profiles of patients who underwent fluoropyrimidine-based chemotherapy were collected, and their TIIC fractions were calculated and clustered. Differentially expressed genes (DEGs) between clusters were used to calculate the TMEscore. The association between the TMEscore, chemotherapy response, and survival rate was analyzed. Machine learning methods were used to identify key TMEscore-related genes, and a gene signature was constructed to verify the predictive value.ResultsTwo clusters based on the TIIC fraction were identified, and the TMEscore was calculated based on the DEGs of the two clusters. The TMEscore was higher in patients who responded to chemotherapy than in those who did not, and was associated with the survival rate of patients who underwent chemotherapy. Three machine learning methods, support vector machine (SVM), decision tree (DT), and Extreme Gradient Boosting (XGBoost), identified three TMEscore-related genes (ADH1C, SLC26A2, and NANS) associated with the response to chemotherapy. A TMEscore-related gene signature was constructed, and three external cohorts validated that the gene signature could predict the response to chemotherapy. Five datasets and clinical samples showed that the expression of the three TMEscore-related genes was increased in tumor tissues compared to those in control tissues.ConclusionsThe TIIC-based TMEscore was associated with the survival of CRC patients who underwent fluoropyrimidine-based chemotherapy, and predicted the response to chemotherapy. The TMEscore-related gene signature had a better predictive value for response to chemotherapy than for survival.

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Section: Resultsmentioning

confidence: 99%

Tumor-infiltrating immune cells based TMEscore and related gene signature is associated with the survival of CRC patients and response to fluoropyrimidine-based chemotherapy

Guo

Lei

et al. 2022

Front. Oncol.

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“…Both the MAYA and the ARETHUSA study are therapeutically exploiting the hypermutant state induced by the alkylating agent temozolamide by inactivating mutations in MMR genes, thereby sensitizing a subset of MMRp CRC tumors with O-6 Methylguanine-DNA Methyltransferase (MGMT) methylation to ICIs. 8 Likewise, the observation that targeted therapy against the epidermal growth factor receptor ( EGFR )/ BRAF V600E increased DNA damage and induced adaptive mutability in preclinical models has led to clinical trials combining anti-EGFR/BRAF targeted therapy with ICI. 9 This report by Amodio et al.…”

Section: Main Textmentioning

confidence: 99%

Harnessing the therapeutic vulnerability of MMR heterogeneity in colorectal cancer

Anandappa

Overman

2023

Cell Reports Medicine

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“…The potential predictive role of TMB in mCRC was also investigated in a subgroup of MSS CRC patients associated with O6-Methylguanine-DNA-methyltransferase (MGMT)-deficiency, showing as using temozolomide led to the appearance of neo mutations and tumor neoantigens, prompting to immunotherapy effectiveness [ 86 , 87 ].…”

Section: Long-standing and Emerging Immune Biomarkers In Crcmentioning

confidence: 99%

New Potential Immune Biomarkers in the Era of Precision Medicine: Lights and Shadows in Colorectal Cancer

Damato

Rotolo

Caputo

et al. 2022

Life

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Genetic alterations in CRC have shown a negative predictive and prognostic role in specific target therapies. The onset of immunotherapy has also undergone remarkable therapeutic innovation, although limited to a small subgroup of patients, the MSI-H/dMMR, which represents only 5% of CRC. Research is moving forward to identify whether other biomarkers can predict response to ICIs, despite various limitations regarding expression and identification methods. For this purpose, TMB, LAG3, and PD-L1 expression have been retrospectively evaluated in several solid tumors establishing the rationale to design clinical trials with concurrent inhibition of LAG3 and PD-1 results in a significant advantage in PFS and OS in advanced melanoma patients. Based on these data, there are clinical trials ongoing in the CRC as well. This review aims to highlight what is already known about genetic mutations and genomic alterations in CRC, their inhibition with targeted therapies and immune checkpoints inhibitors, and new findings useful to future treatment strategies.

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Temozolomide Treatment Alters Mismatch Repair and Boosts Mutational Burden in Tumor and Blood of Colorectal Cancer Patients

Cited by 52 publications

References 92 publications

Tumor-infiltrating immune cells based TMEscore and related gene signature is associated with the survival of CRC patients and response to fluoropyrimidine-based chemotherapy

Tumor-infiltrating immune cells based TMEscore and related gene signature is associated with the survival of CRC patients and response to fluoropyrimidine-based chemotherapy

Harnessing the therapeutic vulnerability of MMR heterogeneity in colorectal cancer

New Potential Immune Biomarkers in the Era of Precision Medicine: Lights and Shadows in Colorectal Cancer

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